-
Drugs Oct 2021The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased... (Review)
Review
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
Topics: Animals; Antifungal Agents; Drug Development; Drug Interactions; Drug Resistance, Fungal; Fungi; Humans; Invasive Fungal Infections
PubMed: 34626339
DOI: 10.1007/s40265-021-01611-0 -
Drugs in R&D Mar 2022On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as... (Review)
Review
On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as vaginal yeast infection. Ibrexafungerp is the first drug approved in a novel antifungal class in more than two decades, and the Food and Drug Administration's decision was based on positive results from two pivotal phase III studies in which oral ibrexafungerp proved both safe and effective in patients with vulvovaginal candidiasis. The decision was also based on substantial preclinical and clinical work in both the pharmacokinetics and pharmacodynamics of ibrexafungerp. This paper reviews that research and looks ahead to explore how this novel antifungal agent may be used in the future to address the expanding problem of drug-resistant mycotic infections.
Topics: Antifungal Agents; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes; United States
PubMed: 34961907
DOI: 10.1007/s40268-021-00376-x -
Virulence Aug 2017Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes... (Review)
Review
Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes and minimize selective pressure and adverse events. Antifungal utilization has steadily risen over time in concert with the increase in number of immunocompromised adults and children at risk for invasive fungal infections (IFI). Challenges in diagnosing IFI often lead to delays in treatment and poorer outcomes. There are also emerging data linking prior antifungal exposure and suboptimal dosing to the emergence of antifungal resistance, particularly for Candida. Antimicrobial stewardship programs can take a multi-pronged bundle approach to ensure suitable prescribing of antifungals via post-prescription review and feedback and/or prior authorization. Institutional guidelines can also be developed to guide diagnostic testing in at-risk populations; appropriate choice, dose, and duration of antifungal agent; therapeutic drug monitoring; and opportunities for de-escalation and intravenous-to-oral conversion.
Topics: Adult; Antifungal Agents; Antimicrobial Stewardship; Candida; Candidiasis; Child; Drug Monitoring; Drug Resistance, Fungal; Humans; Immunocompromised Host; Invasive Fungal Infections; Microbial Sensitivity Tests; Pediatrics
PubMed: 27588344
DOI: 10.1080/21505594.2016.1226721 -
Virulence Feb 2017With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be... (Review)
Review
With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.
Topics: Animals; Antifungal Agents; Drug Discovery; Enzyme Inhibitors; Fluconazole; Fungi; Glucosyltransferases; Humans; Metabolic Networks and Pathways; Mycoses; Trehalose
PubMed: 27248439
DOI: 10.1080/21505594.2016.1195529 -
Frontiers in Cellular and Infection... 2022Invasive fungal diseases (IFD) are a major global public health concern. The incidence of IFD has increased the demand for antifungal agents. Isavuconazole (ISA) is a... (Review)
Review
PURPOSE
Invasive fungal diseases (IFD) are a major global public health concern. The incidence of IFD has increased the demand for antifungal agents. Isavuconazole (ISA) is a new triazole antifungal agent that has shown promising efficacy in the prophylaxis and treatment of invasive fungal diseases. The aim of this review is to summarize the recent real-world experiences of using ISA for the treatment and prevention of IFD.
METHODS
We performed a comprehensive literature search of the MEDLINE, PubMed, Embase, and Cochrane databases for clinical applications of ISA in the real world. Tables and reference lists are presented for this systematic review.
RESULTS
IFD poses a major threat to public health and causes high mortality rates. ISA may provide a good treatment. For example, the efficacy of ISA in the treatment of invasive aspergillosis (IA) is comparable to that of voriconazole, and its efficacy in the treatment of invasive mucormycosis (IM) is similar to that of liposomal amphotericin B (L-AmB); therefore, ISA is recommended as the first-line treatment for IA and IM. ISA can also achieve good efficacy in the treatment of invasive candidiasis (IC) and can be used as an alternative to de-escalation therapy after first-line drug therapy. In addition, most studies have shown the efficacy and safety of ISA for the prophylaxis of IFD.
CONCLUSION
Taken together, ISA are expected to become a new choice for the treatment and prevention of IFD because of their good tolerability, high bioavailability, and few drug interactions.
Topics: Humans; Triazoles; Invasive Fungal Infections; Nitriles; Antifungal Agents; Aspergillosis; Mucormycosis; Candidiasis, Invasive
PubMed: 36530445
DOI: 10.3389/fcimb.2022.1049959 -
Archives of Oral Biology Mar 2021To determine the phytochemical composition of Byrsonima gardneriana (A. Juss) leaf extract (BGE) and its antifungal activity against Candida spp., antioxidant potential...
OBJECTIVE
To determine the phytochemical composition of Byrsonima gardneriana (A. Juss) leaf extract (BGE) and its antifungal activity against Candida spp., antioxidant potential and in vitro cytotoxicity.
MATERIAL AND METHODS
BGE was obtained and submitted to Gas Chromatography Coupled to Mass Spectrometry for phytochemical analysis. The ethanolic extract was tested for its antifungal activity against C. albicans and non-albicans reference strains and clinical isolates in addition to inhibition of C. albicans growth kinetics. It was also tested for antioxidant potential in the presence of phenylhydrazine and reactive oxygen species (ROS). And cytoxicity in human erythrocytes. The data were analyzed by one-way Analysis of Variance (ANOVA) followed by Tukey's or Dunnett's post-hoc test, with α = 0.05.
RESULTS
Pyroglutamic acid (90.77 %), eucalyptol (89.61 %) and octanoic acid (76.22 %) were the major compounds detected in BGE, P (%) is the percent probability of compound identification, according to the mass spectra library. The extract showed fungistatic activity, with MIC of 125 μg/mL against most tested strains. While BGE showed low hemolytic activity on all blood types tested herein, it could not prevent osmotic stress in human erythrocytes. The extract did not have oxidizing effects in the presence of phenylhydrazine, but it showed antioxidant potential against ROS when tested at 31 μg/mL and 62 μg/mL.
CONCLUSION
B. gardneriana extract showed antifungal activity against Candida spp., demonstrated low hemolytic potential, no oxidant activity in human erythrocytes and antioxidant activity against ROS. This study opens avenues for the study of BGE as a promising biocompatible antifungal agent.
Topics: Antifungal Agents; Antioxidants; Candida; Erythrocytes; Gas Chromatography-Mass Spectrometry; Hemolysis; Humans; Malpighiaceae; Microbial Sensitivity Tests; Phytochemicals; Plant Extracts
PubMed: 33472099
DOI: 10.1016/j.archoralbio.2020.104994 -
Frontiers in Cellular and Infection... 2022Fungal populations are commonly found in natural environments and present enormous health care challenges, due to increased resistance to antifungal agents. Paeonol...
Fungal populations are commonly found in natural environments and present enormous health care challenges, due to increased resistance to antifungal agents. Paeonol exhibits antifungal activities; nevertheless, the antifungal and antibiofilm activities of paeonol against and remain largely unexplored. Here, we aimed to evaluate the antifungal and antibiofilm activities of paeonol against and/or (i.e., against mono- or dual-species). The minimum inhibitory concentrations (MICs) of paeonol for mono-species comprising or were 250 μg ml, whereas the MIC values of paeonol for dual-species were 500 μg ml. Paeonol disrupted cell membrane integrity and increased the influx of gatifloxacin into cells of mono- and dual-species cells, indicating an antifungal mode of action. Moreover, paeonol at 8 times the MIC damaged mono- and dual-species cells within and biofilms, as it did planktonic cells. In particular, at 4 and 8 mg ml, paeonol efficiently dispersed preformed 48-h biofilms formed by mono- and dual-species cells, respectively. Paeonol inhibited effectively the yeast-to-hyphal-form transition of and impaired capsule and melanin production of . The addition of 10 MIC paeonol to the medium did not shorten the lifespan of , and 2 MIC paeonol could effectively protect the growth of and -infected . Furthermore, RNA sequencing was employed to examine the transcript profiling of and biofilm cells in response to 1/2 MIC paeonol. RNA sequencing data revealed that paeonol treatment impaired biofilm formation of by presumably downregulating the expression level of initial filamentation, adhesion, and growth-related genes, as well as biofilm biosynthesis genes, whereas paeonol inhibited biofilm formation of by presumably upregulating the expression level of ergosterol biosynthesis-related genes. Together, the findings of this study indicate that paeonol can be explored as a candidate antifungal agent for combating serious single and mixed infections caused by and .
Topics: Acetophenones; Animals; Antifungal Agents; Biofilms; Caenorhabditis elegans; Candida albicans; Cryptococcosis; Cryptococcus neoformans; Microbial Sensitivity Tests
PubMed: 35669114
DOI: 10.3389/fcimb.2022.884793 -
International Journal of Molecular... Jan 2018Undecylenic acid (UA), known as antifungal agent, still cannot be used to efficiently modify commercial dental materials in such a way that this affects . Actually,...
Undecylenic acid (UA), known as antifungal agent, still cannot be used to efficiently modify commercial dental materials in such a way that this affects . Actually, issues with infections and fungal resistance compromise the use of Poly(methyl-methacrylate) (PMMA) as dental material. The challenge remains to turn PMMA into an antifugal material, which can ideally affect both sessile (attached) and planktonic (free-floating) cells. We aimed to tackle this challenge by designing PMMA-UA composites with different UA concentrations (3-12%). We studied their physico-chemical properties, the antifungal effect on and the cytotoxicity toward human cells. We found that UA changes the PMMA surface into a more hydrophilic one. Mainly, as-preparation composites with ≥6% UA reduced sessile for >90%. After six days, the composites were still efficiently reducing the sessile cells (for ~70% for composites with ≥6% UA). Similar results were recorded for planktonic . Moreover, the inhibition zone increased along with the UA concentration. The antifungal effect of UA was also examined at the surface of an UA-loaded agar and the minimal inhibitory concentration (MIC90) was below the lowest-studied 0.0125% UA. Furthermore, the embedded filamentation test after 24 h and 48 h showed complete inhibition of the growth at 0.4% UA.
Topics: Antifungal Agents; Candida albicans; Cell Line, Tumor; Cell Survival; Humans; Polymethyl Methacrylate; Undecylenic Acids
PubMed: 29316713
DOI: 10.3390/ijms19010184 -
Drug Design, Development and Therapy 2021The resistance of to traditional antifungal drugs brings a great challenge to clinical treatment. To overcome the resistance, developing antifungal agent sensitizers...
PURPOSE
The resistance of to traditional antifungal drugs brings a great challenge to clinical treatment. To overcome the resistance, developing antifungal agent sensitizers has attracted considerable attention. This study aimed to determine the anti- activity of BEH alone or BEH-FLC combination and to explore the underlying mechanisms.
MATERIALS AND METHODS
In vitro antifungal effects were performed by broth microdilution assay and XTT reduction assay. Infected larvae model was used to determine the antifungal effects in vivo. Probes Fluo-3/AM, FITC-VAD-FMK and rhodamine 6G were used to study the influence of BEH and FLC on intracellular calcium concentration, metacaspase activity and drug efflux of .
RESULTS
BEH alone exhibited obvious antifungal activities against . BEH plus FLC not only showed synergistic effects against planktonic cells and preformed biofilms within 8 h but also enhanced the antifungal activity in infected larvae. Mechanistic studies indicated that antifungal effects of drugs might be associated with the increasement of calcium concentration, activation of metacaspase activity to reduce virulence and anti-biofilms, but were not related to drug efflux.
CONCLUSION
BEH alone or combined with FLC displayed potent antifungal activity both in vitro and in vivo, and the underlying mechanisms were related to reduced virulence factors.
Topics: Animals; Antifungal Agents; Benserazide; Biofilms; Candida albicans; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Drug Therapy, Combination; Fluconazole; Microbial Sensitivity Tests; Moths
PubMed: 34815665
DOI: 10.2147/DDDT.S336667 -
Indian Pediatrics Dec 2005Voriconazole (VRZ) is a second-generation triazole antifungal agent active against many species of Aspergillus and Candida and acts by inhibiting ergosterol synthesis....
Voriconazole (VRZ) is a second-generation triazole antifungal agent active against many species of Aspergillus and Candida and acts by inhibiting ergosterol synthesis. VRZ has less nephrotoxicity and less infusion-related toxicity than that of Amphotericin B. Oral and parental formulation have similar pharmacokinetics and thus oral formulation shortens the duration of hospital stay. It is overall well tolerated but has significant drug interactions.
Topics: Antifungal Agents; Aspergillosis; Candidiasis; Drug Interactions; Humans; Pyrimidines; Triazoles; Voriconazole
PubMed: 16424557
DOI: No ID Found